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Coble et al., 2005

Coble, J., Arbuckle, T., Lee, W., Alavanja, M., & Dosemeci, M.; “The validation of a pesticide exposure algorithm using biological monitoring results;” Journal of Occupational and Environmental Hygiene, 2005, 2(3), 194-201; DOI: 10.1080/15459620590923343.

ABSTRACT:

A pesticide exposure algorithm was developed to calculate pesticide exposure intensity scores based on responses to questions about pesticide handling procedures and application methods in a self-administered questionnaire. The validity of the algorithm was evaluated through comparison of the algorithm scores with biological monitoring data from a study of 126 pesticide applicators who applied the herbicides MCPA or 2,4-D. The variability in the algorithm scores calculated for these applicators was due primarily to differences in their use of personal protective equipment (PPE). Rubber gloves were worn by 75% of applicators when mixing and 22% when applying pesticides, rubber boots were worn by 33% when mixing and 23% when applying, and goggles were worn by 33% and 17% of applicators when mixing and when applying, respectively. Only 2% of applicators wore all three types of PPE when both mixing and applying, and 15% wore none of these three types of PPE when either mixing or applying. Substantial variability was also observed in the concentrations of pesticides detected in the post application urine samples. The concentration of MCPA detected in urine samples collected on the second day after the application ranged from less than < 1.0 to 610 microg/L among 84 of the applicators who applied MCPA. The concentrations of 2,4-D detected in the urine samples ranged from less than < 1.0 to 514 microg/L among 41 of the applicators who applied 2,4-D. When categorized into three groups based on the algorithm scores, the geometric mean in the highest exposure group was 20 microg/L compared with 5 microg/L in the lowest exposure group for the MCPA applicators, and 29 microg/L in highest exposure group compared with 2 microg/L in the low exposure group for the 2,4-D applicators. A regression analysis detected statistically significant trends in the geometric mean of the urine concentrations across the exposure categories for both the 2,4-D and the MCPA applicators. The algorithm scores, based primarily on the use of PPE, appear to provide a reasonably valid measure of exposure intensity for these applicators, however, further studies are needed to generalize these results to other types of pesticides and application methods. FULL TEXT

Alexander et al., 2017

Alexander, M., Koutros, S., Bonner, M. R., Barry, K. H., Alavanja, M. C. R., Andreotti, G., Byun, H. M., Chen, L., Beane Freeman, L. E., Hofmann, J. N., Kamel, F., Moore, L. E., Baccarelli, A., & Rusiecki, J.; “Pesticide use and LINE-1 methylation among male private pesticide applicators in the Agricultural Health Study;” Environ Epigenet, 2017, 3(2), dvx005; DOI: 10.1093/eep/dvx005.

ABSTRACT:

Cancer risk may be associated with DNA methylation (DNAm) levels in Long Interspersed Nucleotide Element 1 (LINE-1), a surrogate for global DNAm. Exposure to certain pesticides may increase risk of particular cancers, perhaps mediated in part through global DNAm alterations. To date, human data on pesticide exposure and global DNAm alterations are limited. The goal of this study was to evaluate alterations of LINE-1 DNAm by pesticides in a variety of classes. Data from 596 cancer-free male participants enrolled in the Agricultural Health Study (AHS) were used to examine associations between use of 57 pesticides and LINE-1 DNAm measured via Pyrosequencing in peripheral blood leucocytes. Participants provided information on pesticide use at three contacts between 1993 and 2010. Associations of ever/never pesticide use and lifetime days of application (years of use x days per year) and LINE-1 DNAm level were assessed using linear regression, adjusting for potential confounders (race, age at blood draw, and frequency of drinking alcohol) and other moderately correlated pesticides. After adjustment, ever application of 10 pesticides was positively associated and ever application of eight pesticides was negatively associated with LINE-1 DNAm. In dose-response analyses, increases in five pesticides (imazethapyr, fenthion, EPTC, butylate, and heptachlor) were associated with increasing LINE-1 DNAm (ptrend < 0.05) and increases in three pesticides (carbaryl, chlordane, and paraquat) were associated with decreasing LINE-1 DNAm (ptrend < 0.05). This study provides some mechanistic insight into the pesticide-cancer relationship, which may be mediated in part by epigenetics. FULL TEXT

Thomas et al., 2010

Thomas, K. W., Dosemeci, M., Hoppin, J. A., Sheldon, L. S., Croghan, C. W., Gordon, S. M., Jones, M. L., Reynolds, S. J., Raymer, J. H., Akland, G. G., Lynch, C. F., Knott, C. E., Sandler, D. P., Blair, A. E., & Alavanja, M. C.; “Urinary biomarker, dermal, and air measurement results for 2,4-D and chlorpyrifos farm applicators in the Agricultural Health Study;” Journal of Exposure Science and Environmental Epidemiology, 2010, 20(2), 119-134; DOI: 10.1038/jes.2009.6.

ABSTRACT:

A subset of private pesticide applicators in the Agricultural Health Study (AHS) epidemiological cohort was monitored around the time of their agricultural use of 2,4-dichlorophenoxyacetic acid (2,4-D) and O,O-diethyl-O-3,5,6-trichloro-2-pyridyl phosphorothioate (chlorpyrifos) to assess exposure levels and potential determinants of exposure. Measurements included pre- and post-application urine samples, and patch, hand wipe, and personal air samples. Boom spray or hand spray application methods were used by applicators for 2,4-D products. Chlorpyrifos products were applied using spray applications and in-furrow application of granular products. Geometric mean (GM) values for 69 2,4-D applicators were 7.8 and 25 microg/l in pre- and post-application urine, respectively (P<0.05 for difference); 0.39 mg for estimated hand loading; 2.9 mg for estimated body loading; and 0.37 microg/m(3) for concentration in personal air. Significant correlations were found between all media for 2,4-D. GM values for 17 chlorpyrifos applicators were 11 microg/l in both pre- and post-application urine for the 3,5,6-trichloro-2-pyridinol metabolite, 0.28 mg for body loading, and 0.49 microg/m(3) for air concentration. Only 53% of the chlorpyrifos applicators had measurable hand loading results; their median hand loading being 0.02 mg. Factors associated with differences in 2,4-D measurements included application method and glove use, and, for hand spray applicators, use of adjuvants, equipment repair, duration of use, and contact with treated vegetation. Spray applications of liquid chlorpyrifos products were associated with higher measurements than in-furrow granular product applications. This study provides information on exposures and possible exposure determinants for several application methods commonly used by farmers in the cohort and will provide information to assess and refine exposure classification in the AHS. Results may also be of use in pesticide safety education for reducing exposures to pesticide applicators. FULL TEXT

Hoppin et al., 2002

Hoppin, Jane A., Umbach, David M, London, Stephanie J., Alavanja, Michael, & Sandler, Dale P.; “Chemical Predictors of Wheeze among Farmer Pesticide Applicators in the Agricultural Health Study;” American Journal of Respiratory and Critical Care Medicine, 2002, 165, 683-689; DOI: 10.1164/rccm.2106074.

ABSTRACT:

Pesticides may contribute to respiratory symptoms among farmers. Using the Agricultural Health Study, a large cohort of certified pesticide applicators in Iowa and North Carolina, we explored the association between wheeze and pesticide use in the past year. Self-administered questionnaires contained items on 40 currently used pesticides and pesticide application practices. A total of 20,468 applicators, ranging in age from 16 to 88 years, provided complete information; 19% reported wheezing in the past year. Logistic regression models controlling for age, state, smoking, and history of asthma or atopy were used to evaluate associations between individual pesticides and wheeze. Among pesticides suspected to contribute to wheeze, paraquat, three organophosphates (parathion, malathion, and chlorpyrifos), and one thiocarbamate (S-ethyl-dipropylthiocarbamate [EPTC]) had elevated odds ratios (OR). Parathion had the highest OR (1.5, 95% confidence interval [CI] 1.0, 2.2).

Chlorpyrifos, EPTC, paraquat, and parathion demonstrated significant dose–response trends. The herbicides, atrazine and alachlor, but not 2,4-D, were associated with wheeze. Atrazine had a significant dose–response trend with participants applying atrazine more than 20 days/year having an OR of 1.5 (95% CI 1.2,1.9). Inclusion of crops and animals into these models did not significantly alter the observed OR. These associations, though small, suggest an independent role for specific pesticides in respiratory symptoms of farmers. FULL TEXT

Dosemeci et al., 2002

Dosemeci, M., Alavanja, M. C., Rowland, A. S., Mage, D., Zahm, S. H., Rothman, N., Lubin, J. H., Hoppin, J. A., Sandler, D. P., & Blair, A.; “A quantitative approach for estimating exposure to pesticides in the Agricultural Health Study;” Annals of Occupational Hygiene, 2002, 46(2), 245-260; DOI: 10.1093/annhyg/mef011.

ABSTRACT:

We developed a quantitative method to estimate long-term chemical-specific pesticide exposures in a large prospective cohort study of more than 58000 pesticide applicators in North Carolina and Iowa. An enrollment questionnaire was administered to applicators to collect basic time- and intensity-related information on pesticide exposure such as mixing condition, duration and frequency of application, application methods and personal protective equipment used. In addition, a detailed take-home questionnaire was administered to collect further intensity-related exposure information such as maintenance or repair of mixing and application equipment, work practices and personal hygiene. More than 40% of the enrolled applicators responded to this detailed take-home questionnaire. Two algorithms were developed to identify applicators’ exposure scenarios using information from the enrollment and take-home questionnaires separately in the calculation of subject-specific intensity of exposure score to individual pesticides. The ‘general algorithm’ used four basic variables (i.e. mixing status, application method, equipment repair status and personal protective equipment use) from the enrollment questionnaire and measurement data from the published pesticide exposure literature to calculate estimated intensity of exposure to individual pesticides for each applicator. The ‘detailed’ algorithm was based on variables in the general algorithm plus additional exposure information from the take-home questionnaire, including types of mixing system used (i.e. enclosed or open), having a tractor with enclosed cab and/or charcoal filter, frequency of washing equipment after application, frequency of replacing old gloves, personal hygiene and changing clothes after a spill. Weighting factors applied in both algorithms were estimated using measurement data from the published pesticide exposure literature and professional judgment. For each study subject, chemical-specific lifetime cumulative pesticide exposure levels were derived by combining intensity of pesticide exposure as calculated by the two algorithms independently and duration/frequency of pesticide use from the questionnaire. Distributions of duration, intensity and cumulative exposure levels of 2,4-D and chlorpyrifos are presented by state, gender, age group and applicator type (i.e. farmer or commercial applicator) for the entire enrollment cohort and for the sub-cohort of applicators who responded to the take-home questionnaire. The distribution patterns of all basic exposure indices (i.e. intensity, duration and cumulative exposure to 2,4-D and chlorpyrifos) by state, gender, age and applicator type were almost identical in two study populations, indicating that the take-home questionnaire sub-cohort of applicators is representative of the entire cohort in terms of exposure. FULL TEXT

Alavanja et al., 1996

Alavanja, M. C., Sandler, D. P., McMaster, S. B., Zahm, S. H., McDonnell, C. J., Lynch, C. F., Pennybacker, M., Rothman, N., Dosemeci, M., Bond, A. E., & Blair, A.; “The Agricultural Health Study;” Environmental Health Perspectives, 1996, 104(4), 362-369; DOI: 10.1289/ehp.96104362.

ABSTRACT:

The Agricultural Health Study, a large prospective cohort study has been initiated in North Carolina and Iowa. The objectives of this study are to: 1) identify and quantify cancer risks among men, women, whites, and minorities associated with direct exposure to pesticides and other agricultural agents; 2) evaluate noncancer health risks including neurotoxicity reproductive effects, immunologic effects, nonmalignant respiratory disease, kidney disease, and growth and development among children; 3) evaluate disease risks among spouses and children of farmers that may arise from direct contact with pesticides and agricultural chemicals used in the home lawns and gardens, and from indirect contact, such as spray drift, laundering work clothes, or contaminated food or water; 4) assess current and past occupational and nonoccupational agricultural exposures using periodic interviews and environmental and biologic monitoring; 5) study the relationship between agricultural exposures, biomarkers of exposure, biologic effect, and genetic susceptibility factors relevant to carcinogenesis; and 6) identify and quantify cancer and other disease risks associated with lifestyle factors such as diet, cooking practices, physical activity, smoking and alcohol consumption, and hair dye use. In the first year of a 3-year enrollment period, 26,235 people have been enrolled in the study, including 19,776 registered pesticide applicators and 6,459 spouses of registered farmer applicators. It is estimated that when the total cohort is assembled in 1997 it will include approximately 75,000 adult study subjects. Farmers, the largest group of registered pesticide applicators comprise 77% of the target population enrolled in the study. This experience compares favorably with enrollment rates of previous prospective studies. FULL TEXT

Zuanazzi et al., 2020

Zuanazzi, N. R., Ghisi, N. C., & Oliveira, E. C.; “Analysis of global trends and gaps for studies about 2,4-D herbicide toxicity: A scientometric review;” Chemosphere, 2020, 241, 125016; DOI: 10.1016/j.chemosphere.2019.125016.

ABSTRACT:

2,4-dichlorophenoxyacetic acid (2,4-D) is a herbicide that is used worldwide in agricultural and urban activities to control pests, reaching natural environments directly or indirectly. The research on 2,4-D toxicology and mutagenicity has advanced rapidly, and for this reason, this review summarizes the available data in Web of Science (WoS) to provide insights into the specific characteristics of 2,4-D toxicity and mutagenicity. Contrary to traditional reviews, this study uses a new method to quantitatively visualize and summarize information about the development of this field. Among all countries, the USA was the most active contributor with the largest publication and centrality, followed by Canada and China. The WoS categories ‘Toxicology’ and ‘Biochemical and Molecular Biology’ were the areas of greatest influence. 2,4-D research was strongly related to the keywords glyphosate, atrazine, water and gene expression. The studies trended to be focused on occupational risk, neurotoxicity, resistance or tolerance to herbicides, and to non-target species (especially aquatic ones) and molecular imprinting. In general, the authors have worked collaboratively, with concentrated efforts, allowing important advances in this field. Future research on 2,4-D toxicology and mutagenicity should probably focus on molecular biology, especially gene expression, assessment of exposure in human or other vertebrate bioindicators, and pesticide degradation studies. In summary, this scientometric analysis allowed us to make inferences about global trends in 2,4-D toxicology and mutagenicity, in order to identify tendencies and gaps and thus contribute to future research efforts.

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Pardo et al., 2020

Pardo, L. A., Beane Freeman, L. E., Lerro, C. C., Andreotti, G., Hofmann, J. N., Parks, C. G., Sandler, D. P., Lubin, J. H., Blair, A., & Koutros, S.; “Pesticide exposure and risk of aggressive prostate cancer among private pesticide applicators;” Environmental Health, 2020, 19(1), 30; DOI: 10.1186/s12940-020-00583-0. https://www.ncbi.nlm.nih.gov/pubmed/32138787.

ABSTRACT:

BACKGROUND: Prostate cancer (PCa) is one of the most commonly diagnosed cancers among men in developed countries; however, little is known about modifiable risk factors. Some studies have implicated organochlorine and organophosphate insecticides as risk factors (particularly the organodithioate class) and risk of clinically significant PCa subtypes. However, few studies have evaluated other pesticides. We used data from the Agricultural Health Study, a large prospective cohort of pesticide applicators in North Carolina and Iowa, to extend our previous work and evaluate 39 additional pesticides and aggressive PCa.

METHODS: We used Cox proportional hazards models, with age as the time scale, to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between ever use of individual pesticides and 883 cases of aggressive PCa (distant stage, poorly differentiated grade, Gleason score >/= 7, or fatal prostate cancer) diagnosed between 1993 and 2015. All models adjusted for birth year, state, family history of PCa, race, and smoking status. We conducted exposure-response analyses for pesticides with reported lifetime years of use.

RESULTS: There was an increased aggressive PCa risk among ever users of the organodithioate insecticide dimethoate (n = 54 exposed cases, HR = 1.37, 95% CI = 1.04, 1.80) compared to never users. We observed an inverse association between aggressive PCa and the herbicide triclopyr (n = 35 exposed cases, HR = 0.68, 95% CI = 0.48, 0.95), with the strongest inverse association for those reporting durations of use above the median (>/= 4 years; n = 13 exposed cases, HR=0.44, 95% CI=0.26, 0.77).

CONCLUSION: Few additional pesticides were associated with prostate cancer risk after evaluation of extended data from this large cohort of private pesticide applicators.

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Lerro et al., 2020

Lerro, C. C., Andreotti, G., Wong, J. Y., Blair, A., Rothman, N., & Beane Freeman, L. E.; “2,4-D exposure and urinary markers of oxidative DNA damage and lipid peroxidation: a longitudinal study;” Occupational and Environmental Medicine, 2020, 77(4), 276-280; DOI: 10.1136/oemed-2019-106267.

ABSTRACT:

OBJECTIVE: 2,4-Dichlorophenoxyacetic acid (2,4-D) is a herbicide that is commonly used commercially, agriculturally and residentially worldwide. There is concern about its potential for carcinogenicity based on studies in laboratory animals demonstrating the potential for induction of oxidative stress. We conducted a longitudinal biomarker study of 31 pesticide applicators in Kansas who heavily applied 2,4-D and 34 non-applicator controls.

METHODS: We used multivariable generalised linear mixed-effect models to evaluate the association between urinary 2,4-D and natural log-transformed 8-iso prostaglandin F2alpha (8-isoprostane) and 8-hydroxy-2′-deoxyguanosine (8-OHdG), adjusting for urinary creatinine, age, tobacco use and concomitant use of the herbicide picloram.

RESULTS: Compared with non-applicator controls, urinary 2,4-D in the third quartile of exposure was associated with elevated 8-isoprostane (e (beta)=1.38, 95% CI 1.03 to 1.84). There was no association among the highest exposed and no exposure-response trend. 2,4-D exposure was not associated with 8-OHdG. Results were unchanged when restricted to participants who only applied 2,4-D (no picloram use).

CONCLUSIONS: We did not find evidence that increasing 2,4-D exposure was associated with 8-isoprostane or 8-OHdG. Future work should carefully evaluate potential confounders of this association, such as diet and physical activity, as well as additional biological markers of oxidative stress and damage. FULL TEXT

Lerro et al., 2020

Lerro, C. C., Hofmann, J. N., Andreotti, G., Koutros, S., Parks, C. G., Blair, A., Albert, P. S., Lubin, J. H., Sandler, D. P., & Beane Freeman, L. E.; “Dicamba use and cancer incidence in the agricultural health study: an updated analysis;” International Journal of Epidemiology, 2020; DOI: 10.1093/ije/dyaa066.

ABSTRACT:

BACKGROUND: The herbicide dicamba has been commonly used agriculturally and residentially. Recent approval of genetically engineered dicamba-resistant crops is expected to lead to increased dicamba use, and there has been growing interest in potential human health effects. A prior analysis in the Agricultural Health Study (AHS) suggested associations between dicamba and colon and lung cancer. We re-evaluated dicamba use in the AHS, including an additional 12 years and 2702 exposed cancers.

METHODS: The AHS is a prospective cohort of pesticide applicators in Iowa and North Carolina. At enrollment (1993–1997) and follow-up (1999–2005), participants reported dicamba use. Exposure was characterized by cumulative intensity-weighted lifetime days, including exposure lags of up to 20 years. We estimated relative risks (RR) and 95% confidence intervals (CI) using multivariable Poisson regression for incident cancers diagnosed from enrollment through 2014/2015.

RESULTS: Among 49 922 applicators, 26 412 (52.9%) used dicamba. Compared with applicators reporting no dicamba use, those in the highest quartile of exposure had elevated risk of liver and intrahepatic bile duct cancer (nexposed = 28, RRQ4 = 1.80, CI: 1.26–2.56, Ptrend < 0.001) and chronic lymphocytic leukaemia (CLL, nexposed = 93, RRQ4 = 1.20, CI: 0.96–1.50, Ptrend = 0.01) and decreased risk of myeloid leukaemia (nexposed = 55, RRQ4 = 0.73, CI: 0.51–1.03, Ptrend = 0.01). The associations for liver cancer and myeloid leukaemia remained after lagging exposure of up to 20 years.

CONCLUSIONS: With additional follow-up and exposure information, associations with lung and colon cancer were no longer apparent. In this first evaluation of liver and intrahepatic bile duct cancer, there was an association with increasing use of dicamba that persisted across lags of up to 20 years. FULL TEXT

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